Dicarboxylic acid salt of sibutramine

ABSTRACT

Disclosed is a novel dicarboxylic acid salt of sibutramine, which has good physicochemical properties. Also disclosed are a method of preparing the compound and a pharmaceutical composition comprising the compound.

TECHNICAL FIELD

The present invention relates to a novel dicarboxylic acid salt ofsibutramine, a method of preparing the compound, and a pharmaceuticalcomposition comprising the compound as an effective ingredient.

BACKGROUND ART

Sibutramine(N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine),which is a inhibitor of 5-hydroxytryptamine and noradrenaline reuptakein vivo (Neuropharmacology, 28, p 129-134), is useful in the treatmentof depression, Parkinson's disease, obesity, insulin-independentdiabetes mellitus, epilepsy, and the like. In addition, sibutraminereduces body weight gain by a dual action to reduce food intake byenhancing satiety and to increase energy expenditure by stimulating heatgeneration (Int. J. Obesity, 19, p 145; Brit. J. Pharmacol. 114, p 388).The therapeutic use of sibutramine in depression is described in BritishPatent Specification 2098602. The therapeutic use of sibutramine inParkinson's disease is disclosed in International Pat. Publication No.WO88/06444. The therapeutic use of sibutramine in cerebral functiondisorders is disclosed in U.S. Pat. No. 4,939,175. The use ofsibutramine hydrochloride in the treatment of obesity is disclosed inEuropean Pat. No. 397831. Also, International Pat. Publication No.WO95/20949 discloses the use of sibutramine for improving impairedglucose tolerance or glucose tolerance in patients suffering frominsulin-independent diabetes mellitus.

Typically, the preparation of salts having pharmaceutically usefulphysical properties must satisfy the following physicochemical criteria:(1) good solubility, (2) good stability, (3) good non-hygroscopicity and(4) compressibility into tablet form.

However, Korean Pat. Publication No. 94-8913 states that sibutraminehydrochloride has been known to contain a variable amount of water andthus be hygroscopic, and that non-hygroscopic sibutramine can beobtained by preparing sibutramine hydrochloride in a monohydrate form.Sibutramine hydrochloride monohydrate has been prepared by brining itinto contact with a medium consisting of water or a medium containingwater. Since sibutramine is difficult to purify due to its low meltingpoint, it is preferable to use a crystalline material capable of beingpurified by recrystallization in order to prepare a pharmaceuticalcomposition comprising sibutramine. Korean Pat. Publication No.1990-0000274 discloses that sibutramine is utilized as salts formed withacids providing non-toxic acid addition salts containingpharmaceutically acceptable anions, for example, in the form ofhydrochloride, malate, acetate, citrate, fumarate, tartrate, succinate,aspartate or glutmate salt.

However, since sibutramine hydrochloride is difficult to handlepharmaceutically due to its hygroscopic nature, it is undesirable to usesibutramine hydrochloride for preparing medicaments. In the preparationof medicaments, a constant weight of an active compound should becontained in each dosage form, but an active ingredient absorbing waterfrom the surrounding environment makes it difficult to achieve suchconsistency. Korean Pat. Publication No. 94-8913 discloses that whensibutramine hydrochloride is prepared in a monohydrate form, anon-hygroscopic product is obtained, which is suitable for thepreparation of capsules, tablets and other pharmaceutical dosage forms.This patent publication describes that sibutramine hydrochloridemonohydrate can be prepared by contacting sibutramine hydrochloride witha medium consisting of or containing water, which is a water-immisciblesolvent or a water-miscible solvent.

The currently used sibutramine hydrochloride monohydrate is prepared bya complicated process including adding a predetermined amount of waterto a reaction mixture, or including preparing sibutramine hydrochlorideanhydrate and suspending the sibutramine hydrochloride anhydrate in awater-containing solvent for a long time with agitation. In addition,since sibutramine hydrochloride monohydrate has relatively lowsolubility between pH 1.0 and pH 7.4, substitute salts having bettersolubility need to be developed in order to improve the bioavailabilityof sibutramine.

In this regard, intensive and through research into the development ofnovel salts of sibutramine, capable of solving the problems encounteredin the prior art, conducted by the present inventors, resulted in thefinding that among dicarboxylic acid salts of sibutramine, sibutramineoxalate and sibutramine malonate in anhydrous forms, which do notrequire a complicated process for preparing a hydrate, possessremarkably high solubility in water, and also exhibit non-hygroscopicityand stability.

DISCLOSURE OF THE INVENTION

It is therefore an object of the present invention to provide adicarboxylic acid salt of sibutramine.

It is another object of the present invention to provide a method ofpreparing the dicarboxylic acid salt of sibutramine.

It is a further object of the present invention to provide apharmaceutical composition for treating and preventing pathologicalstates of obesity and related disorders, comprising the dicarboxylicacid salt of sibutramine as an active ingredient. It is yet anotherobject of the present invention to provide a pharmaceutical compositionfor treating depression, Parkinson's disease, insulin-independentdiabetes mellitus or epilepsy, comprising the dicarboxylic acid salt ofsibutramine as an active ingredient.

It is yet another object of the present invention to provide a method oftreating and preventing pathological states of obesity and relateddisorders, and a method of treating depression, Parkinson's disease,insulin-independent diabetes mellitus or epilepsy, these methods beingbased on administering the pharmaceutical composition comprising thedicarboxylic acid salt of sibutramine as an active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and other advantages of thepresent invention will be more clearly understood from the followingdetailed description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 is a powder X-ray diffraction spectrum of sibutramine oxalateaccording to the present invention;

FIG. 2 is a powder X-ray diffraction spectrum of sibutramine malonateaccording to the present invention;

FIG. 3 is a differential scanning calorimeter thermogram of sibutramineoxalate according to the present invention; and

FIG. 4 is a differential scanning calorimeter thermogram of sibutraminemalonate according to the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

In one aspect, the present invention relates to a dicarboxylic acid saltof sibutramine, represented by the following Chemical Formula 1:

wherein, n is an integral number of 0 or 1.

The compound of Chemical Formula 1 includes sibutramine oxalaterepresented by Chemical Formula 2, below, and sibutramine malonaterepresented by Chemical Formula 3, below.

The term “sibutramine”, as used herein, refers to racemic sibutramine,unless otherwise noted.

The sibutramine oxalate and sibutramine malonate according to thepresent invention exhibit remarkably high solubility in water comparedto the known sibutramine hydrochloride monohydratand, and also displaynon-hygroscopicity and chemical stability to heat and light. Inparticular, oxalic acid and malonic acid used in the preparation ofsalts are advantageous because they have high safety and low toxicity,relative to hydrochloric acid used in the preparation of sibutraminehydrochloride monohydrate. These acids are pharmaceutically acceptablesalts which have been used in various medicaments, and especially, havebeen safely used in medicines for treating circulatory disorders,including nafronyl, naftidrofuryl and perazine.

TABLE 1 LD₅₀ in mouse (i.p.) LD₅₀ in rat (oral) Remarks HCl 40 mg/kg 900mg/kg Malonic acid 300 mg/kg 1310 mg/kg Oxalic acid 155 mg/kg — Sodiumsalt

The dicarboxylic acid salts of sibutramine according to the presentinvention may be crystalline or non-crystalline. Crystalline forms ofthe dicarboxylic acid salts of sibutramine are preferred inconsideration of physical properties such as non-hygroscopicity andthermodynamical stability.

In detail, the crystalline sibutramine oxalate of Chemical Formula 2 ischaracterized by having an X-ray diffraction pattern in which peaks(I/I₀≧200) appear at 2θ values of 5.46, 10.92, 12.16, 12.74, 14.92,15.44, 15.78, 17.4, 19.24, 21.3, 22.0, 22.92, 24.54, 25.3, 25.8, 27.52,28.74, 28.92, 30.12, 33.26, 35.04, and 39.76.

The crystalline sibutramine malonate of Chemical Formula 3 ischaracterized by having an X-ray diffraction pattern in which peaks(I/I₀≧200) appear at 2θ values of 7.7, 10.74, 11.08, 11.56, 15.42,15.78, 17.24, 17.84, 18.1, 19.02, 19.68, 21.54, 21.9, 22.24, 22.88,23.26, 23.64, 24.44, 24.72, 26.0, 27.6, 28.4, 28.62, and 29.3.

In anther aspect, the present invention relates to a method of preparingthe dicarboxylic acid salt of sibutramine.

In detail, the present invention includes a method of preparing adicarboxylic acid salt of sibutramine, comprising reacting sibutraminewith a dicarboxylic acid selected from among oxalic acid and malonicacid in an inert solvent.

In a detailed practice, the reaction of sibutramine with oxalic acid ormalonic acid takes place according to Reaction 1, below.

In the method, oxalic acid and malonic acid may be used in an amount of1 to 2 molar equivalents, and preferably 1.1 to 1.2 molar equivalents,relative to one molar equivalent of sibutramine. Typically, oxalic acidor malonic acid is added in a solid state to an organic solvent in whichsibutramine is dissolved, dissolved in an organic solvent in whichsibutramine is dissolved, or added in droplets thereto after beingdissolved in another organic solvent.

In the method, the organic solvent may be used in an amount of 3 to 20ml, and preferably 5 to 15 ml, relative to 1 g of sibutramine.

The organic solvent used in the method is a mixture of one or more estersolvents, selected from the group consisting of ethyl acetate, n-propylacetate, isopropylacetate and n-butyl acetate, and one or more alcoholsolvents, selected from the group consisting of methanol, ethanol,propanol, butanol and isopropanol, or is one selected from among thesolvents.

The method is performed at a reaction temperature ranging from 0° C. tothe boiling point of a solvent, and preferably at a temperature of 15 to35° C. Also, after oxalic acid or malonic acid is added, the reaction ispreferably allowed to take place for 0.5 to 6 hours.

Sibutramine oxalate and sibutramine malonate of Chemical Formulas 2 and3, respectively, prepared according to the method have greatly enhancedsolubility in water while exhibiting almost the same non-hygroscopicityand stability to water and heat as does sibutramine hydrochloridemonohydrate, which is conventionally used as an acid addition salt.Owing to such enhanced water solubility, the dicarboxylic acid salt ofsibutramine according to the present invention has a good release ratecharacteristic from a composition comprising the same, and thus hasbetter bioavailability.

The present invention relates to a pharmaceutical composition comprisinga therapeutically effective amount of a dicarboxylic acid salt ofsibutramine and a pharmaceutically acceptable diluent or carrier, and amethod of treating or preventing diseases by administering thecomposition. In an aspect, the present invention includes apharmaceutical composition for treating or preventing pathologicalstates of obesity and related disorders, comprising a therapeuticallyeffective amount of a dicarboxylic acid salt of sibutramine and apharmaceutically acceptable diluent or carrier, and a method of treatingor preventing pathological states of obesity and related disorders usingthis composition.

The present invention also includes a pharmaceutical composition fortreating depression, comprising a therapeutically effective amount of adicarboxylic acid salt of sibutramine and a pharmaceutically acceptablediluent or carrier, and a method of treating depression by administeringthis composition.

The present invention further includes a pharmaceutical composition fortreating or preventing Parkinson's disease, comprising a therapeuticallyeffective amount of a dicarboxylic acid salt of sibutramine and apharmaceutically acceptable diluent or carrier, and a method of treatingor preventing Parkinson's disease by administering this composition.

The present invention still further includes a pharmaceuticalcomposition for treating insulin-independent diabetes mellitus,comprising a therapeutically effective amount of a dicarboxylic acidsalt of sibutramine and a pharmaceutically acceptable diluent orcarrier, and a method of treating insulin-independent diabetes mellitusby administering this composition.

The present invention still further includes a pharmaceuticalcomposition for treating epilepsy, comprising a therapeuticallyeffective amount of a dicarboxylic acid salt of sibutramine and apharmaceutically acceptable diluent or carrier, and a method of treatingepilepsy by administering this composition.

The pharmaceutical composition comprising the dicarboxylic acid salt ofsibutramine according to the present invention as an active ingredientmay be preferably administered orally, for example in the form oftablets or capsules.

Tablets may be prepared by mixing an active ingredient with a carrier, adiluent or an excipient and compressing the mixture into tablets.Examples of suitable carriers, diluents or excipients includedisintegrators such as starch, sugars and mannitol; fillers andextenders such as calcium phosphate and silicic derivatives; bindingagents such as carboxymethyl cellulose and other cellulose derivatives,gelatin and polyvinyl pyrrolidone; and lubricants such as talc, calciumand magnesium stearate, and solid polyethylene glycol. Also, hard orsoft gelatin capsules containing an active ingredient, either with orwithout an additive such as the carriers, diluents or excipients may beprepared according to an ordinary method.

The pharmaceutical composition preferably contains a crystallinedicarboxylic acid salt of sibutramine, represented by Chemical Formula1, as an active ingredient in an amount of 1 to 50 parts by weight basedon 250 parts by weight of the composition. For example, thepharmaceutical composition having a total weight of 250 mg according tothe present invention may be prepared in such a manner as to contain 10mg (based on sibutramine content) of the crystalline dicarboxylic acidsalt of sibutramine, represented by Chemical Formula 1, 115 mg ofmicrocrystalline cellulose, 115 mg of lactose, 5 mg of silicon dioxide,and 5 mg of magnesium stearate. However, this composition of thepharmaceutical composition is illustrative, and thus, the scope of thepresent invention is not limited thereto.

A better understanding of the present invention may be obtained throughthe following examples which are set forth to illustrate, but are not tobe construed as the limit of the present invention.

EXAMPLES

Sibutramine oxalate and sibutramine malonate according to the presentinvention were prepared, and were compared with sibutraminehydrochloride hydrate for physical properties including hygroscopicity,solubility, stability, light stability and crystallizability. Inaddition, sibutramine oxalate and sibutramine malonate were formulatedinto capsules in order to examine their formulability and releasepatterns.

Reference Example 1 Preparation of Sibutramine Hydrochloride Monohydrate

Sibutramine hydrochloride anhydrate was prepared according to a methoddescribed in Korean Pat. Publication No. 90-00274. Then, according to amethod described in Korean Pat. Publication No. 94-08913, 10 g of theprepared sibutramine hydrochloride anhydrate was dissolved in a boilingmixture of 110 ml acetone and 1.2 ml water, and the resulting solutionwas hot-filtered and distilled to remove 80 ml of the solvent, thusreducing the volume of the filtrate. The concentrate was filtered torecover a generated solid. The solid was vacuum-dried, thus obtaining9.2 g (yield: 87%) of the compound of Chemical Formula 2, which had amelting point of 195° C.

Example 1 Preparation of Sibutramine Oxalate

15 g of sibutramine was dissolved in 60 ml of methanol. Oxalic acid(5.07 g) dissolved in 20 ml methanol was slowly added in droplets to thesibutramine solution at room temperature and agitated for 2 hrs. Theresulting solution was cooled to 0° C., agitated for about 2 hrs, andfiltered to collect deposited crystals. The crystals were washed with 50ml of isopropyl ether and vacuum-dried at 50° C., thus obtaining 18 g(yield: 89.7%) of a white target compound.

TABLE 2 Elemental analysis (C₁₉H₂₈ClNO₄) Unit (%) Measured value C:61.88, H: 7.87, N: 3.81, O: 17.63 Theoretical value C: 61.7,  H: 7.63,N: 3.79, O: 17.30

Melting point: 150.4° C.

¹H-NMR (DMSO-d6): 1.0 (6H, dd), 1.4 (2H, t), 1.6˜1.8 (2H, m), 1.9 (1H,m), 2.4 (2H, m), 2.5 (6H, s), 2.6 (2H, m), 2.7 (2H, m), 3.6 (1H, t), 7.5(4H, dd)

Example 2 Preparation of Sibutramine Malonate

15 g of sibutramine was dissolved in 60 ml of ethyl acetate. Malonicacid (5.72 g) dissolved in 20 ml ethyl acetate was slowly added indroplets to the sibutramine solution at room temperature and agitatedfor 2 hrs. The resulting solution was cooled to 0° C., agitated forabout 2 hrs, and filtered to collect a deposited crystal. The crystalwas washed with 50 ml of isopropyl ether and vacuum-dried at 50° C.,thus obtaining 19 g (yield: 92.6%) of a white target compound.

TABLE 3 Elemental analysis (C₂₀H₃₀ClNO₄) Unit (%) Measured value C:62.75, H: 8.13, N: 3.67, O: 17.12 Theoretical value C: 62.57, H: 7.88,N: 3.65, O: 16.67

Melting point: 152.4° C.

¹H-NMR (DMSO-d6): 0.9 (6H, dd), 1.2 (2H, m), 1.5˜1.8 (2H, m), 1.9 (1H,m), 2.2 (2H, m), 2.3 (6H, s), 2.4 (2H, m), 2.5 (2H, m), 3.1 (2H, s), 3.2(1H, t), 7.4 (4H, m)

Example 3 Non-hygroscopicity Evaluation

The crystalline sibutramine oxalate and sibutramine malonate, preparedin Examples 1 and 2, respectively, and the known sibutraminehydrochloride monohydrate were exposed to humid air at 75% or 95%relative humidity at 25° C. for a period of three days or one week.Then, the water content of the samples was measured using a Karl-Fishertitrator. The results are given in Table 4, below. In Table 4, the watercontent of an active ingredient is expressed as a percentage of watercontent by weight (weight %).

TABLE 4 Storage humidity (relative humidity) at 25° C. 75% 95% Storageperiod Initial 3 days 1 week Sibutramine oxalate 0.02% 0.03% 0.02%Sibutramine malonate 0.03% 0.02% 0.03% Sibutramine HCl monohydrate 5.49%5.49%  5.5%

As shown in Table 4, sibutramine oxalate and sibutramine malonate didnot absorb moisture even in a humid atmosphere of 95% relative humidity,indicating that these compounds have non-moisture-absorbing properties.

Example 4 Solubility Evaluation

The crystalline sibutramine oxalate and sibutramine malonate, preparedin Examples 1 and 2, respectively, and the known sibutraminehydrochloride monohydrate were evaluated for solubility in distilledwater and at several pH values. The results are given in Table 5, below.

TABLE 5 Salt forms of sibutramine HCl monohydrate Oxalate MalonateSolvent (mg/ml) (mg/ml) (mg/ml) Remarks Distilled water 26.18 35.7644.51 Dissolved pH 1.2 13.36 40.64 85.72 at 37° C. pH 4.0 9.58 25.4632.87 pH 5.3 6.58 54.79 17.57 pH 6.8 23.14 34.04 55.42 pH 7.4 9.2 23.4134.63

As shown in Table 5, sibutramine oxalate and sibutramine malonate hadhigh solubility in distilled water and at several pH values. Inparticular, these compounds had high solubility at pH 7.4 within therange of blood pH, indicating that they have good bioavailability.

Example 5 Evaluation of Stability to Heat and Light

The stability of an active ingredient used in a pharmaceuticalcomposition to heat and light is a very important physical propertyduring formulation into tablets and capsules and long-term storage. Inthis regard, sibutramine oxalate and sibutramine malonate were evaluatedfor stability at a high temperature and in the presence of light for apredetermined period of time, and were compared with sibutraminehydrochloride monohydrate for heat stability and photostability. Indetail, each compound was stored at 60° C. After 1, 2 and 4 weeks, theresidual proportion of the initial level of an active ingredient wasmeasured by high performance liquid chromatography (HPLC). The resultsare given in Table 6, below. Also, fluorescent light was radiated at 25°C. using a light stability test chamber suitable for the ICH guideline,and after 1, 2 and 4 weeks, the residual proportion of the initial levelof an active ingredient was measured by HPLC. The results are given inTable 7, below.

TABLE 6 Storage period Initial 1 week 2 weeks 4 weeks HCl monohydrate1.000 1.000 0.999 0.999 Oxalate 1.000 1.000 0.999 0.999 Malonate 1.0001.000 0.999 0.999

TABLE 7 Storage period Initial 1 week 2 weeks 4 weeks HCl monohydrate1.000 1.000 0.999 0.998 Oxalate 1.000 1.000 0.999 0.999 Malonate 1.0001.000 0.999 0.999

As shown in Tables 6 and 7, sibutramine oxalate and sibutramine malonateexhibited heat stability and photostability equal to those ofsibutramine hydrochloride monohydrate.

Example 6 Preparation of Capsules Containing Sibutramine Oxalate

Ingredients were mixed according to the composition described in Table8, below, to prepare capsules containing sibutramine oxalate.

TABLE 8 Ingredients Content (per capsule) Sibutramine oxalate Amountcorresponding to  10 mg of sibutramine Lactose 115 mg Microcrystallinecellulose 115 mg Silicon dioxide  5 mg Magnesium stearate  5 mg

The ingredients were mixed and filled into hard capsules using a capsulefilling machine (Bosche).

Example 7 Preparation of Capsules Containing Sibutramine Malonate

Ingredients were mixed according to the composition described in Table9, below, to prepare capsules containing sibutramine malonate.

TABLE 9 Ingredients Content (per capsule) Sibutramine malonate Amountcorresponding to  10 mg of sibutramine Lactose 115 mg Microcrystallinecellulose 115 mg Silicon dioxide  5 mg Magnesium stearate  5 mg

The ingredients were mixed and filled into hard capsules using a capsulefilling machine (Bosche).

INDUSTRIAL APPLICABILITY

The dicarboxylic acid salts of sibutramine according to the presentinvention have good physicochemical properties includingnon-hygroscopicity, solubility, stability, formulability andcrystallizability. Compared to the known sibutramine hydrochloridemonohydrate, the dicarboxylic acid salts of sibutramine have advantagesof good solubility and simple preparation by a process not requiring anadditional procedure for preparing a hydrate. The advantages furtherinclude that because the present compounds, present in anhydrous forms,do not change in content due to their non-hygroscopic nature, theyguarantee consistency suitable for the preparation of pharmaceuticaldosage forms. Thus, the present compounds may be suitable for long-termstorage. The present compounds also have enhanced bioavailability.

Moreover, since oxalic acid and malonic acid used in the preparation ofthe novel dicarboxylic acid salts of sibutramine are less-toxic acidsthat have been proven to be pharmaceutically safe for long-term use, thenovel dicarboxylic acid salts of sibutramine may be suitable forlong-term administration with no risk of toxicity.

1. A dicarboxylic acid salt of sibutramine, represented by the followingChemical Formula 1:

wherein, n is an integral number of 0 or
 1. 2. The dicarboxylic acidsalt of sibutramine as set forth in claim 1, which is sibutramineoxalate having an X-ray diffraction pattern in which peaks appear at 2θvalues of 5.46, 10.92, 12.16, 12.74, 14.92, 15.44, 15.78, 17.4, 19.24,21.3, 22.0, 22.92, 24.54, 25.3, 25.8, 27.52, 28.74, 28.92, 30.12, 33.26,35.04, and 39.76.
 3. The dicarboxylic acid salt of sibutramine as setforth in claim 1, which is sibutramine malonate having an X-raydiffraction pattern in which peaks appear at 2θ values of 7.7, 10.74,11.08, 11.56, 15.42, 15.78, 17.24, 17.84, 18.1, 19.02, 19.68, 21.54,21.9, 22.24, 22.88, 23.26, 23.64, 24.44, 24.72, 26.0, 27.6, 28.4, 28.62,and 29.3.
 4. A method of preparing a dicarboxylic acid salt ofsibutramine represented by the following Chemical Formula 1:

wherein, n is an integral number of 0 or 1 comprising reactingsibutramine with a dicarboxylic acid selected from among oxalic acid andmalonic acid in an inert solvent.
 5. A pharmaceutical compositioncomprising a dicarboxylic acid salt of sibutramine represented by thefollowing Chemical Formula 1:

wherein, n is an integral number of 0 or 1 as an effective ingredientand a pharmaceutically acceptable diluent or carrier.
 6. Thepharmaceutical composition as set forth in claim 5, which is formulatedinto tablets or capsules.
 7. A method of treating obesity, depression,Parkinson's disease, insulin-independent diabetes mellitus or epilepsy,comprising administering the pharmaceutical composition comprising thedicarboxylic acid salt of sibutramine represented by the followingChemical Formula 1:

wherein, n is an integral number of 0 or 1 as an effective ingredient.8. The pharmaceutical composition as set forth in claim 5, wherein thecomposition is for treating obesity, depression, Parkinson's disease,insulin-independent diabetes mellitus, or epilepsy.